Field of the Invention
The invention relates to categories of good, intermediate and poor prognosis for in vitro fertilization (IVF) according to age of a candidate for IVF. By ascertaining the anti-Müllerian hormone (AMH) level for such a candidate with conventional testing, a diagnosis, and then therapy, in accordance with the invention may be made as to the prognosis category that applies for pregnancy probability, live birth probability or both by matching the tested AMH level with an applicable one of ranges of AMH levels of the prognosis categories in correspondence with the age of the candidate.
The invention then specifically relates to the administration of AMH in view of the logistic regression models that so classify patients or subjects into the good-, intermediate- and poor-prognosis groups or categories. Patients or subjects can be classified into good-, intermediate- and poor-prognosis categories based on clinical pregnancy and live birth rates, using only age and functional ovarian reserve parameters. AMH is expressed by a specific category of follicular cells called granulosa cells of preantral and antral follicles during the reproductive age. AMH acts as a natural follicular gatekeeper limiting follicle growth initiation and maintains the primordial follicle pool throughout the reproductive age.
AMH is also known as a Müllerian inhibiting substance (MIS) and is a member of the large transforming growth factor-beta (TGF beta) family of glycoproteins that are involved in the regulation of growth and differentiation. This family includes AMH agonists, derivatives and other TGF beta agents.
Description of Related Art
The contents of U.S. provisional patent application No. 62/128,127 are incorporated herein by reference pertaining to preparation of a composition having AMH and its administration to a subject. Further, the entire subject matter under the heading “Definitions” of that application are incorporated herein by reference. Furthermore, the term AMH as used in this application includes AMH agonists, AMH derivatives and other TGF beta agents and MISs.
An AMH test may involve taking a blood sample from the subject in a conventional manner and analyzing the blood sample with appropriate conventional laboratory test procedures and equipment. Laboratory test procedures and equipment to ascertain an AMH level are conventionally known. For example, the Becknman Coulter Diagnostics Access AHM Assay may be used in an analysis to ascertain the AMH level of a subject.
For this invention, AMH was assessed with such Generation II (second generation) assays. Those skilled in the art will understand that other generations of assays and conventional test procedures could be used as well. While AMH assays may vary at the extremes of very high or very low AMH levels, they are very similar in the medium and other ranges significant for this invention and application. As will be disclosed, the previously unknown and undisclosed ‘best’ AMH ranges of significance for this invention are similar regardless of the assay used.
What establishes outcome prognoses for infertile women entering IVF cycles is not well defined. That is, IVF cycles currently cannot be reliably prognosticated. The ability to reasonably predict prognoses would be, therefore, clinically valuable. It also would also enhance internal as well as external quality controls, the latter being mandated in the U.S. by an act of Congress and currently not satisfactorily accomplished.
Finally, treatments may demonstrate different levels of efficacy in good-, intermediate- and poor-prognosis patients. Better definition of “disease” severity, therefore, should improve individualization of IVF treatments.
Prognostication of IVF outcomes has been a longstanding goal. Various models have been published, with the key component being female age, as declining clinical pregnancy and live birth rates with advancing female age demonstrate. Therefore, changes in outcomes with advancing female age have to be considered when building prediction models for IVF.
Age is, however, not the only important predictor of IVF outcomes. Functional ovarian reserve (FOR), a term reflecting the growing follicle pool, and, therefore, oocyte and embryo numbers, is also closely associated with IVF outcomes. Abnormally low FOR (LFOR) is defined by abnormally increased age-specific follicle stimulating hormone (FSH) and/or decreased age-specific AMH, both reflecting declining egg and embryo numbers and, therefore, deteriorating pregnancy and live birth chances.
In women with premature ovarian aging (POA), also called occult primary ovarian insufficiency (oPOI), normal statistical associations between age and FOR are disturbed. POA/oPOI patients prematurely demonstrate LFOR. They, independent of race and ethnicity, represent approximately 10% of females and often more than half of all patients in IVF centers. FOR—rather than age-based models may, therefore, be preferable in POA patients.
Protocols for administration of AMH to women and girls have been proposed.
Average serum AMH is approximately 4 nanograms/milliliter (4 ng/ml) in healthy young women with normal ovarian reserve. Kelsey T W, Wright P, Nelson S M, Anderson R A, Wallace W H. A validated model of serum anti-mullerian hormone from conception to menopause. PloS one 2011; 6:e22024.
The half-life of AMH is 27.6 hrs. Griesinger G, Dafopoulos K, Buendgen N, Cascorbi I, Georgoulias P, Zavos A, Messini C I, Messinis I E. Elimination half-life of anti-Mullerian hormone. The Journal of clinical endocrinology and metabolism 2012; 97:2160-2163.
A time period of 90-120 days is the approximate time from primary follicle recruitment to ovulation. McGee E A, Hsueh A J. Initial and cyclic recruitment of ovarian follicles. Endocrine reviews 2000; 21:200-214
For women with low ovarian reserve who are pursuing controlled ovarian hyperstimulation (COH) for fertility treatment, there is a proposed protocol.
The proposed protocol is pretreatment with AMH prior to COH and is intended to improve follicular synchrony, oocyte yield and pregnancy rates with fertility treatments. Starting dose of AMH is 4 to 8 ng/ml daily×typical volume (5,500 ml)=22,000 to 44,000 ng/day for 90 days. The dose and duration may require adjustments based on future studies, patient size as well as other parameters. This treatment would be followed by a short washout period ranging from days to weeks. The short washout period would be followed by controlled ovarian hyperstimulation (commonly used agents include: gonadotropins, selective estrogen-receptor modulators, and aromatase inhibitors) and then followed by either Intrauterine Insemination or Oocyte Retrieval for In IVF or for Oocyte/Embryo cryopreservation.
For women and girls who are pursuing fertility preservation due to imminent exposure to gonadotoxic treatments, there is a further proposed protocol.
The further proposed protocol is treatment with AMH prior to and contemporaneously with gonadotoxic treatments and is intended to decrease activation and recruitment of primordial follicles via a so-called “burnout” effect, which induces rapid and often complete loss of ovarian reserve via follicle depletion. Recruitment adds follicles to the pool of so-called growing follicles, which, in contrast to primordial follicles, are very sensitive to damage from chemotherapy drugs and/or radiotherapy. Kalich-Philosoph L, Roness H, Carmely A, Fishel-Bartal M, Ligumsky H, Paglin S, Wolf I, Kanety H, Sredni B, Meirow D. Cyclophosphamide triggers follicle activation and “burnout”; AS101 prevents follicle loss and preserves fertility. Science translational medicine 2013; 5:185ra162.
By preventing follicle activation, AMH potentially protects the gonads from chemotherapy and radiation therapy by keeping follicles at primordial stages, where they are less sensitive to damage, thereby preventing loss of fertility as a consequence of gonadotoxic treatments, as currently seen in cancer patients and in other medical conditions requiring such treatments.
The starting dose of AMH is 4 to 8 ng/ml daily×typical adult volume (5,500 ml)=22,000 to 44,000 ng/day. Dose and duration may require adjustments based on future studies, patient size as well as other parameters. Lower doses may be appropriate for pediatric patients. Treatment with AMH is initiated several days prior to and continued during gonadotoxic treatment, AMH should be continued until gonadotoxic treatment is stopped.
There is a need to understand the affects of AMH levels on pregnancy rates, birth rates and miscarriage rates sufficient to administer AMH in a manner to control such rates. There is no basis in the prior art to control AMH at certain levels, as opposed to simply increasing AMH levels, in order to promote candidacy for IVF and/or to increase pregnancy, live birth and/or miscarriage rates. If such administration would be to achieve and/or maintain a certain AMH level, regardless of other hormones such as FSH and other treatments, an entirely new area of therapeutic utility for AMH would be disclosed and taught. This, in part, is the subject matter of this invention.